In ex vivo gene therapy, autologous or allogenic cells are transfected in vitro and infused back into the patient following their expansion in the culture medium. Paulk N.K., Pekrun K., Zhu E., Nygaard S., Li B., Xu J., Chu K., Leborgne C., Dane A.P., Haft A., et al. Indigenous Genetics and Rare Diseases: Harmony, Diversity and Equity. The DNA sequences transported by AAV vectors are stabilized in an episomal form, so that long-term expression is only possible through delivery into long-living postmitotic cells. As regards the CRISPR/Cas9 tool, the variable part is nucleotide-based (RNA) rather than protein-based. Atchison R.W., Casto B.C., Hammon W. McD. AAV-based gene therapies for the treatment of HA are at an earlier stage of development than those for HB. Pediatric Hematology - Orlando Health Hemophilia Gene Therapy: Key Principles | Pfizer The current treatment of choice for hemophilia is fundamentally based on intravenous prophylactic replacement of the deficient factor by exogenous recombinant factors, characterized by their longer half-lives, their robust safety profile against emerging pathogens and their high efficacy. Several phase 1 and phase 2 studies have tested the effectiveness of Fitusiran in patients with hemophilia with or without inhibitors; phase 3 trials are now underway with the same goal in mind. Miesbach W., Pasi K.J., Pipe S.W., Hermans C., OMahony B., Guelcher C., Steiner B., Skinner M.W. As regards transfection vectors, gene therapy can be classified into viral and non-viral. FIX expression persisted for at least 20 weeks and immunogenicity remained unchanged. Levels of circulating factor and any bleeding episodes will also be recorded from the start. Although gene therapy protocols are in general more efficient than cell therapy ones, they may be associated with a higher incidence of adverse events, derived mainly from the viral transfection vector used. Production of longer half-life recombinant coagulation factors capable of reducing dosing frequency has also greatly contributed to reducing costs, with comparable clinical outcomes [50]. The Arrival of Gene Therapy for Patients with Hemophilia A Residual factor activity is usually well correlated with patients clinical characteristics. The result is better clotting factor activity, which protects against bleeding. One should be directed at the development of new, less immunogenic serotypes, and the other at the standardization of the clinical dose of vector to be administered. A clinical trial sponsored by the St. Jude Childrens Research Hospital in patients with HB, which used a scAAV2/8-LP1-hFIXco vector, was the first to confirm the long-term benefit of gene therapy with this kind of AAV vector [63,64]. U.S. National Library of Medicine HOPE-B: Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults with Hemophilia B. ClinicalTrials.gov Identifier: NCT01687608. Gene Therapy for Inherited Bleeding Disorders. He Q., Wang H.-H., Cheng T., Yuan W.-P., Ma Y.-P., Jiang Y.-P., Ren Z.-H. Genetic Correction and Hepatic Differentiation of Hemophilia B-Specific Human Induced Pluripotent Stem Cells. Modified autologous stem cells (YUVA-GT-F901). One of the currently most widely accepted hypotheses is that CD8+ lymphocytes may play an important role in the subjects immune response against the vector capsid, eliminating the hepatocytes infected by the virus and triggering an ensuing reduction in the levels of the transgene and of the circulating therapeutic protein. Last year in December, the drugmaker met its main goal in a late-stage study for a hemophilia B gene therapy. These therapies are intended to modify the translation of messenger RNA, inhibiting or modifying production of the protein without affecting the encoding gene [29]. Daniel H.D.-J., Kumar S., Kannangai R., Lakshmi K.M., Agbandje-Mckenna M., Coleman K., Srivastava A., Srivastava A., Abraham A.M. Concizumab, a humanized monoclonal antibody targeted against TFPI, is the most highly developed of these strategies. T Cell-Mediated Immune Responses to AAV and AAV Vectors. This replacement therapy can be given to treat a bleeding episode in progress. [36] reported two AAV serotypes (NP40 and NP59) capable of improving in vivo transduction of human hepatocytes in murine models. Nonetheless, immunosuppressive drugs are associated with metabolic side effects and with an increased overinfection risk. Clotting factors are proteins in blood that help the body stop bleeds. They are partially integrative vectors associated with a low risk of insertional mutagenesis. Even if gene therapy protocols are often more effective than those of cell therapy, they are associated with significant difficulties and a greater number of adverse events, mainly related to the transfer vector. It indicates the number of molecules of the therapeutic protein produced per day by each genome of the administered vector (vg). Toon K., Bentley E.M., Mattiuzzo G. More than Just Gene Therapy Vectors: Lentiviral Vector Pseudotypes for Serological Investigation. Although treatments based on advanced therapies are costly, several economic forecasting studies have demonstrated that they could become less costly than the currently used regimens. a AAV, adeno-associated viral vector. As a potential cure for hemophilia, the new advanced therapies are also associated with a high cost, which limits their applicability and raises doubts about their cost-effectiveness and their equitable administration to patients with hemophilia worldwide, ensuring what the WHO has called the absence of avoidable and remediable differences between groups of people [51]. [52] carried out a study to evaluate the economics of gene therapy in patients with severe HA as compared with prophylaxis with exogenous FVIII using a Markov state-transition model to estimate the costs and efficacy of treatment of severe HA in the United States. Ertl H.C.J. The main treatment for severe hemophilia involves replacing the clotting factor you need through a tube in a vein. Pursuing this strategy will require a definition of variables (serotype/dose of the viral vector, manufacturing techniques) capable of controlling the integration capacity of the different vectors and/or the immune response against the AAV capsid, as well as an evaluation of the patients quality of life defined as an improvement in those outcomes that are most relevant for the patients (chronic pain, yearly infusion rate, mental health). This means that it acts by decreasing the amplification of FXa generation and intrinsic thrombin generation by FVa and FVIIIa proteolysis. Simioni P., Tormene D., Tognin G., Gavasso S., Bulato C., Iacobelli N.P., Finn J.D., Spiezia L., Radu C., Arruda V.R. Although HA and HB are considered clinically indistinguishable, several recent studies have questioned this idea, suggesting that patients with HB could be less prone to severe bleeds than those with HA with the same plasma levels of residual factor (identical disease phenotypes) [2]. Towards a Global Multidisciplinary Consensus Framework on Haemophilia Gene Therapy: Report of the 2nd World Federation of Haemophilia Gene Therapy Round Table. Current replacement. Gene therapy in hemophilia A: a cost-effectiveness analysis This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, hemophilia, advanced therapies, gene therapy, FVIII transgene, FIX transgene, adeno-associated virus, lentiviral vectors, {"type":"clinical-trial","attrs":{"text":"NCT02035605","term_id":"NCT02035605"}}, {"type":"clinical-trial","attrs":{"text":"NCT03520712","term_id":"NCT03520712"}}, {"type":"clinical-trial","attrs":{"text":"NCT02576795","term_id":"NCT02576795"}}, {"type":"clinical-trial","attrs":{"text":"NCT03370913","term_id":"NCT03370913"}}, {"type":"clinical-trial","attrs":{"text":"NCT04323098","term_id":"NCT04323098"}}, {"type":"clinical-trial","attrs":{"text":"NCT03001830","term_id":"NCT03001830"}}, {"type":"clinical-trial","attrs":{"text":"NCT03370172","term_id":"NCT03370172"}}, {"type":"clinical-trial","attrs":{"text":"NCT04370054","term_id":"NCT04370054"}}, {"type":"clinical-trial","attrs":{"text":"NCT03061201","term_id":"NCT03061201"}}, {"type":"clinical-trial","attrs":{"text":"NCT02396342","term_id":"NCT02396342"}}, {"type":"clinical-trial","attrs":{"text":"NCT03489291","term_id":"NCT03489291"}}, {"type":"clinical-trial","attrs":{"text":"NCT03569891","term_id":"NCT03569891"}}, {"type":"clinical-trial","attrs":{"text":"NCT01687608","term_id":"NCT01687608"}}, {"type":"clinical-trial","attrs":{"text":"NCT04394286","term_id":"NCT04394286"}}, {"type":"clinical-trial","attrs":{"text":"NCT00979238","term_id":"NCT00979238"}}, {"type":"clinical-trial","attrs":{"text":"NCT03307980","term_id":"NCT03307980"}}, {"type":"clinical-trial","attrs":{"text":"NCT03861273","term_id":"NCT03861273"}}, {"type":"clinical-trial","attrs":{"text":"NCT03217032","term_id":"NCT03217032"}}, {"type":"clinical-trial","attrs":{"text":"NCT03961243","term_id":"NCT03961243"}}. To be effective, these programs require the participation of academically experienced specialists [43]. There are different approaches to gene therapy, including gene transfer and gene editing. Plasma concentrations of the FIX-R338L protein are normal but its clotting activity is approximately eight times higher than normal. b FVIII, factor VIII. Last year in December, the drugmaker met its main goal in a late-stage study for a hemophilia B gene therapy. Verdera H.C., Kuranda K., Mingozzi F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Chapin J.C., Monahan P.E. ClinicalTrials.gov Identifier: NCT04723680. The severity of HA and HB is contingent on the functional levels of the corresponding circulating factors, with levels of FVIII or FIX below 1% considered diagnostic of severe hemophilia, levels between 1 and 5% diagnostic of moderate hemophilia and those between 5% and 40% of mild hemophilia. Indeed, the use of AAV vectors has provided extraordinarily promising results in terms of the clotting factors concentrations and expression times. Against the background of the imminent approval and release of gene therapy drugs addressed to patients with hemophilia, the WFH saw the need to carry out this initiative at a global scale. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Persons with mild or moderate factor deficiencies may experience spontaneous bleeding, with excessive bleeds occurring only after trauma or an invasive medical procedure. Adachi H., Hengesbach M., Yu Y.-T., Morais P. From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies. Pfizer Announces Positive Marstacimab Results from Pivotal Phase 3 However, it must be said that retrovirus (RNA virus)-based vectors are practically absent from clinical practice despite their high transduction efficacy and their ability to maintain transgene expression over time. Several gene-editing tools are currently in use, such as transcription activator-like effector nucleases (TALENs), zinc finger nucleases (ZFNs) and CRISPR/Cas9 [26,27]. Gene therapy treatments based on siRNA (small interference RNA) are also being developed. [61] obtained long-term efficacy and optimal clinical and histological results in 15 adult subjects with severe HA who had received different doses of a single infusion of AAV5-hFVIII-SQ. Gene Therapy for Hemophilia A and Hemophilia B - Everyday Health Given emicizumabs unique structure, its effect is not likely to be neutralized by inhibitors against FVIII. Bethesda, MD 20894, Web Policies The Cost-Effectiveness of Gene Therapy for Severe Hemophilia B: Microsimulation Study from the United States Perspective. For me, it's the perfect blend of primary care, critical care, and specialty medicine. A phase 1 clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT02035605","term_id":"NCT02035605"}}NCT02035605) demonstrated a 6189% dose-dependent decrease in AT, which was correlated with increased thrombin generation in patients with HA and patients with HB without inhibitors. [81,82] tested a new modification of the Padua variant of FIX. Study demonstrates statistically significant and clinically relevant reduction in annualized bleeding rate compared to prophylaxis and on-demand intravenous regimens Marstacimab, if approved, has the potential to become the first once-weekly subcutaneous treatment for people living with hemophilia B and the first treatment administered as a flat dose for people living with hemophilia A or B A . [73] recently applied protein fusion engineering to design a FIX-HSA (human serum albumin) variant that lengthens the half-life of the FIX molecule. A functional cure means that patients should live as normal a life as possible, with minimum joint impairment, an absence of spontaneous bleeds, normal mobility, an ability to overcome minor trauma without requiring surgery or any other intervention and normal hemostasis. Hart D.P., Branchford B.R., Hendry S., Ledniczky R., Sidonio R.F., Ngrier C., Kim M., Rice M., Minshall M., Arc C., et al. Although it is passed down from parents to children, about 1/3 of cases found have no previous family history. Australian drugmaker CSL Ltd's gene therapy Hemgenix offers a long-term solution for hemophilia B patients, but is among the world's most expensive treatments. Recent work in gene therapy aimed at developing a treatment for congenital coagulopathies has instilled renewed hope in patients with HA and HB [4]. The new gene therapy protocols will require hospital pharmacy departments to revise their storage, handling and reconstitution processes. This kind of vector derives from a native non-pathogenic and barely immunogenic AAV of the parvovirus family which, given its inability to replicate, requires an auxiliary virus to do so [33]. Paulk et al. It will also be necessary to keep a detailed record of patients with hemophilia receiving gene therapy across the world in order to track expected, unexpected and unknown safety issues and obtain a better insight into the maintenance of the protocols efficacy in the long term. TEG was developed and first described by Dr. Hellmut Hartert at the University of Heidelberg (Germany) in 1948. The lessons learned from treating hemophilia will inform advances in gene therapy of other inherited disorders. This antibody binds to activated factor X (FXa) and to activated FIX (FIXa) simulating the function of FVIII. Milwaukee, June 16, 2020 - Patients are now able to participate in a phase I, first-in-human FDA approved clinical trial seeking a potential long-term treatment for Severe Hemophilia A, using a gene therapy that targets synthesis of coagulation Factor Eight (FVIII), which is stored and released from blood platelets at the site of an injured blood vessel. Moreover, pre-existing antibodies against AAVs significantly affect the use of AAV vectors even in the presence of relatively low levels of neutralizing antibodies from natural parvovirus infections. The authors evaluated the stability and long-term safety of the expression of the transgene in 10 patients with severe HB, all of whom were infused with a single dose of AAV8 vector. Nevertheless, this has not happened without significant controversy between its advocates and its critics regarding its promises, limits, possibilities and opportunities. This last possibility, together with the use of variants with a higher clotting ability, such as the Padua variant of FIX (factor IX-R338L), currently represents an exciting alternative for HB patients. Batty P., Lillicrap D. Hemophilia Gene Therapy: Approaching the First Licensed Product. ClinicalTrials.gov Identifier: NCT03370913. Human Gene Therapy for Hemophilia; Guidance for Industry [(accessed on 28 June 2021)]; Konkle B.A., Walsh C.E., Escobar M.A., Josephson N.C., Young G., von Drygalski A., McPhee S.W.J., Samulski R.J., Bilic I., de la Rosa M., et al. Patient-Specific IPSC-Derived Endothelial Cells Provide Long-Term Phenotypic Correction of Hemophilia A. Trinchero A., Sholzberg M., Matino D. The Evolution of Hemophilia Care: Clinical and Laboratory Advances, Opportunities, and Challenges. Robinson M.M., George L.A., Carr M.E., Samelson-Jones B.J., Arruda V.R., Murphy J.E., Rybin D., Rupon J., High K.A., Tiefenbacher S. Factor IX Assay Discrepancies in the Setting of Liver Gene Therapy Using a Hyperfunctional Variant Factor IX-Padua. Anguela X.M., High K.A. The hope is that there will be a genetic cure for hemophilia in the future. A significant (five to eight-fold) reduction in bleeding time and of the total amount of blood lost (approximately four-fold) was obtained compared to R338L-Padua, which allows a faster and more robust hemostatic correction. Most people with hemophilia A have severe disease as manifested by bleeding into the large joints such as the knees or hips. The analysis made in this article is based on some of the clinical trials in progress on HA or HB reported in the ClinicalTrials.gov repository [55] and the European Union Clinical Trials Register [56]. Gene therapy protocols can be applied to somatic cells either in vivo, where correction of the gene, or its insertion into the cells, is performed in the body through a vector; or ex vivo, where correction of the gene, or its insertion, is carried out previously in a series of cells harvested from the patient then reimplanted following an expansion and selection process [20,22]. In hemophilia, protocols based on gene and cell therapy have been shown to hold great potential. Valoctocogene roxaparvovec, the first gene therapy for treatment of hemophilia A, has been granted conditional marketing authorization in Europe. [(accessed on 28 June 2021)]; U.S. National Library of Medicine Dose Confirmation Trial of AAV5-hFIXco-Padua. Pierce G.F., Pasi K.J., Coffin D., Kaczmarek R., Lillicrap D., Mahlangu J., Rottellini D., Sanni T., Srivastava A., VandenDriessche T., et al. Gene therapy for hemophilia A is a one-time infusion that uses a vector to deliver a functional gene to replace the hemophilia patient's own defective gene or a therapeutic gene to provide a missing protein. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A Bolous N.S., Chen Y., Wang H., Davidoff A.M., Devidas M., Jacobs T.W., Meagher M.M., Nathwani A.C., Neufeld E.J., Piras B.A., et al. Pfizer's hemophilia therapy reduces bleeding in late-stage study Some people receive continuous replacement therapy. ICER Publishes Final Report and Policy Recommendations for Hemophilia A The cells used in cell therapy are generally stem cells equipped with a series of special characteristics, such as being undifferentiated, having the ability to self-renew and to differentiate to different cell lines or to different embryonic layers [12,13,14,15]. Innovative Gene Therapy in Hemophilia-A Clinical Trial | Press Release The clinical potential of hemophilia gene therapy has now been pursued for the past 30 years, and there is a realistic expectation that this goal will be achieved within the next couple of years with the licensing of a gene therapy product. A third alternative is to modify the transgene to boost the efficacy of the clotting factor once it has been expressed. This guidance provides recommendations to sponsors developing human gene therapy (GT) products for the treatment of hemophilia including clinical trial design and related development of . Evolution of Haemophilia Integrated Care in the Era of Gene Therapy: Treatment Centres Readiness in United States and EU. However, the problems related to the vectors immunogenicity and hepatotoxicity remain to be solved. One of these clinical trials, sponsored by the Oxford University Hospitals NHS Foundation Trust, will analyze the potential impact of gene therapy on the lives of persons with hemophilia and their family members [57]. Immunosuppression using drugs such as corticosteroids is nowadays necessary to ensure the clinical benefits of AAV-mediated gene transfer. Zhuang W.-Z., Lin Y.-H., Su L.-J., Wu M.-S., Jeng H.-Y., Chang H.-C., Huang Y.-H., Ling T.-Y. Next-generation recombinant products offer a longer half-life, which allows for less frequent dosing and therefore higher adherence to treatment and a better quality of life. Another possibility is to modify the transgene itself to boost the efficiency of the coagulation factor once it has expressed itself. Table 1 shows the recombinant virus vectors used in the different clinical trials for HA and HB, and Table 2 includes a list of the most significant clinical trials in progress on HA and HB. FDA Approves First Gene Therapy to Treat Adults with Hemophilia B Hemophilia is an X-linked monogenic coagulation disorder resulting from a deficiency in coagulation factors in the intrinsic coagulation cascade. BAX 335 Hemophilia B Gene Therapy Clinical Trial Results: Potential Impact of CpG Sequences on Gene Expression. Although the results of AAV-based gene therapy using FIX as a transgene have been encouraging in the context of HB, increases in hepatotoxicity resulting from the loss of expression of the transgene are not uncommon, possibly due to adaptative or innate immune responses against the vectors capsid. Treatment of hemophilia [3] has evolved very rapidly in the last few decades since the advent of plasma and cryoprecipitates; human plasma-derived clotting factor concentrates, and more recently recombinant factors, characterized by a high degree of purity and a longer half-life. Gene therapy for hemophilias: The end of phenotypic testing or the start of a new era? And yet when they might arrive is newly uncertain. Tomeo F., Mariz S., Brunetta A.L., Stoyanova-Beninska V., Penttila K., Magrelli A. Haemophilia, State of the Art and New Therapeutic Opportunities, a Regulatory Perspective. [(accessed on 28 June 2021)]; {"type":"clinical-trial","attrs":{"text":"NCT03369444","term_id":"NCT03369444"}}. Educational programs should be introduced to provide all stakeholders with the information they require about gene therapy as a therapeutic option, including the management of adverse events and the strategies conducive to ensuring the cost-effectiveness of the treatment. Pfizer is developing at least two other therapies for treating hemophilia. Gene Therapy in Hemophilia: Recent Advances - PMC - National Center for This is not an issue in HB as the FIX gene is smaller than the FVIII gene. Precision medicine/personalized medicine: A critical analysis of movements in the transformation of biomedicine in the early 21st century. The choice between a viral or non-viral vector, and between the different kinds of viral vectors available, must be based on a compromise between the phenotypic features of the disease and the therapeutic targets pursued. Although, they exhibit the same low packaging ability as other retroviruses, next-generation LVs, which have been enhanced and endowed with protection from phagocytosis, have been shown to achieve optimal FVIII and FIX expression in the liver [25]. Treatments are about as close to approval as they've ever been. Although further economic studies are required to address this dilemma, it would be misleading to conclude that gene therapy is inherently more costly [54]. There is also considerable uncertainty as to whether payers will be willing to defray the high upfront costs of the one-and-done cure promised by gene therapy, especially considering that reimbursements are normally made based on real world results. However, at the present time, immunogenicity and hepatotoxicity of the transfer vector as well as the problems associated with its integration (insertional mutagenesis) are the most important barriers that must be overcome [21]. HA, with a prevalence of one in every 5000 live births, is more common than HB, which affects one in every 30,000 live births. Khan W.S., Hardingham T.E. Hemophilia is caused by a single gene defect, a minimal expression of FVIII or FIX already leads to major improvement of the bleeding phenotype, and gene expression can be evaluated easily by measuring factor levels in plasma. IPSCs have allowed significant progress in the realm of HA and HB [16,17]. George L.A., Sullivan S.K., Giermasz A., Rasko J.E.J., Samelson-Jones B.J., Ducore J., Cuker A., Sullivan L.M., Majumdar S., Teitel J., et al. SB-FIX is intended to function by placing a corrective copy of the FIX transgene into the genome of the subjects own hepatocytes, under the control of the highly expressed endogenous albumin locus, thereby providing a permanent, liver-specific expression of FIX. At present, patients with hemophilia benefit from palliative treatments providing unprecedented levels of safety and efficacy. Generally, the results of the trials carried out so far on the use of AAVs in patients with HA and HB have yielded promising results. Hemophilia A Treatment: Replacement Therapy and More - Healthline Tang F., Wong H., Ng C.M. Researchers have been working to develop a gene replacement treatment (gene therapy) for Hemophilia A. Hemophilia A (HA) and hemophilia B (HB) are X-linked hereditary hemorrhagic disorders arising from mutations in the genes encoding coagulation factors VIII (FVIII) in HA and IX (FIX) in HB [1]. They may also suffer life-threatening hemorrhagic episodes such as intercranial bleeding. official website and that any information you provide is encrypted Weyand A.C., Grzegorski S.J., Rost M.S., Lavik K.I., Ferguson A.C., Menegatti M., Richter C.E., Asselta R., Duga S., Peyvandi F., et al. Australian drugmaker CSL Ltd's CSL gene therapy Hemgenix offers a long-term solution for hemophilia B patients, but is among the world's most expensive treatments. Pfizer's hemophilia therapy reduces bleeding in late-stage study Top-line results are expected in 2023, and the trial is anticipated to end in July 2026. Received 2021 Jun 30; Accepted 2021 Jul 15. [(accessed on 28 June 2021)]; Pasi K.J., Rangarajan S., Mitchell N., Lester W., Symington E., Madan B., Laffan M., Russell C.B., Li M., Pierce G.F., et al. In a recent clinical trial, Konkle et al. The better results obtained by gene therapy, which showed itself to be less costly and more effective than prophylaxis, could mean that gene therapy-based treatment of severe HA is more economically efficient than prophylaxis with FVIII. Treatment of hemophilia based on plasma-derived products can be very costly, especially if such products are of a recombinant nature [49].